Abstract
MI/R results in endothelial and cardiac contractile dysfunction in the presence of polymorphonuclear leukocytes (PMNs). The role of eNOS in reperfusion injury was studied in a rat PMN‐induced MI/R injury model. Isolated hearts subjected to ischemia (20 min) and reperfused (45 min) with activated PMNs were studied. Cell permeable protein kinase C (PKC) epsilon activator (ε+) or inhibitor (ε‐) peptides were used to increase or decrease eNOS activity respectively. Tetrahydrobiopterin (BH4) or dihydrobiopterin (BH2) are cofactors of eNOS that regulate nitric oxide or superoxide (SO) release respectively. The combination of PKC ε+ (10µM)/BH4 (5µM) (n=7) given during reperfusion significantly restored post‐reperfusion cardiac function compared to I/R PMN hearts (n=11, P <0.01) or PKC ε+ (n=6) or BH4 (n=6) by itself. By contrast, the combination of PKC ε+/BH2 (100µM) (n=6) compromised post‐reperfusion cardiac function suggesting that increased eNOS activity compromises cardiac function when eNOS becomes uncoupled by BH2 or can be cardioprotective when eNOS is coupled to BH4. Moreover, the combination of PKC ε‐ (5µM)/BH2 (n=6) is cardioprotective compared to I/R PMN hearts (P <0.01) or BH2 (n=7) by itself suggesting that decreased eNOS activity during reperfusion attenuates SO release from eNOS. This study was supported by NHLBI Grant 2R15HL‐076235‐02A1 and the Center for the Chronic Disorders of Aging at PCOM.
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